Recent work by several laboratories has indicated that replication stress is a key determinant in the progression towards malignancy. Thus, the activation and recruitment of proteins comprising the replication and DNA damage checkpoints are of critical importance in understanding cancer. These checkpoints are part of a highly concerved set of signaling pathways that are in place to maintain genomic integrity. These pathways are governed by the large protein kinases ATM and ATR, which tranduce the signal from the DNA damage to the cell cycle machinery to halt progression. The ATR kinase responds to lesions caused by UV radiation, replication inhibitors, and other sources of endogeneous and exogeneous damage. The details of recruitment of ATR and its partner protein, ATRIP (ATR-interacting protein) to sites of DNA damage remains unclear. Our preliminary data suggests that two BRCT-repeat containing proteins, BRCA1 and TopBPI, lie upstream of ATR-ATRIP recruitment and activation. Here, we test the hypothesis that BRCT-repeat containg proteins can physically bind to a conserved phosphorylation site in ATRIP and recruit it to sites of DNA damage, and that the loss of this interaction leads to abbrogation of the ATR-mediated checkpoint. [unreadable] [unreadable] [unreadable] [unreadable]